5-Pivaloyloxy-5-(1-phenylethyl) barbituric acid

ABSTRACT

5-Pivaloyloxy-5-(1-phenylethyl) barbituric acid, a method of treating symptoms of pain in warm-blooded animals employing said compound and a therapeutic composition containing same are disclosed.

United States Patent Samour et a1.

[ 51 July 8,1975

5-PIVALOYLOXY-5-( l-PHENYLETHYL) BARBITURIC ACID Inventors: Carlos M.Samour, Wellesley; Julius A. Vida, Billerica, both of Mass.

Assignee: The Kendall Company, Walpole,

Mass.

Filed: July 12, 1973 Appl. No.: 378,482

US. Cl 260/257; 424/254 Int. Cl C07d 51/20 Field of Search 260/257 [56]References Cited FOREIGN PATENTS OR APPLICATIONS 775,117 11/1971 Belgium260/257 Primary ExaminerDonald G. Daus Assistant ExaminerAnne Marie T.Tighe [57] ABSTRACT 1 Claim, No Drawings 1S-PIVALOYLOXY-S-(l-PHENYLETHYL Various S-substituted barbituric acidshave been previously prepared and reported in the literature.'Thus, US.Pat. No. 3,464,990 discloses barbituric acids having certain hydroxyphenylalkyl, lower alkoxy phenylalkyl or aralkoxy phenylalkylsubstituents, together with hydrogen or a lower alkyl, alkenyl oralkynyl group at the -position; these compounds are taught to be usefulas tranquilizers. The synthesis of 5-methyl-5- substituted benzylbarbituric acids is reported by .l. P. Trivedi and .l. J. Trivedi inJournal Indian Chem. Soc., Vol. 35, No. 9, 1958. While nospecifictherapeutic uses for these compounds are disclosed, the purposeof the synthesis was to prepare compounds which would not haveconvulsive properties.

Recently it has been found that a series of 5-substituted-5-phenylalkylbarbituric acids have analgetic properties. These compounds, whichinclude compounds having the formula I but having an acyloxy group of 2to 4 carbon atoms at the 5-position in the barbituric acid ring insteadof the pivaloyloxy group of the compound of this invention, are morefully described in Belgian Pat. No. 775,117, granted Nov. 9, 1971.

While the compounds disclosed in the aforementioned Belgian patent areuseful analgetics, it has now been found that providing a pivaloyloxygroup at the 5-position in the barbituric acid ring markedly enhancesthe therapeutic index of the compounds. By therapeutic index is meantthe LD of a compound divided by its ED or the dose required to killone-half of the test animals divided by the dose required to produce thedesired therapeutic effect in one-half of the test animals. It will beapparent that the larger the therapeutic index, the greater the marginof safety and the more desirable the drug.

The compound of this invention is readily prepared by reacting5-hydroxy-5-( l-phenylethyl) barbituric .acid with a pivaloyl halide(trimethylacetyl halide) in the presence ofa base, such as pyridine,triethylamine, etc. Preparation of 5-hydroxy-5-( l-phenylethyl)barbituric acid is described in Belgian Pat. No. 775,1 17 it is providedby treating 5-(1-phenylethyl) barbituric acid with aqueous hydrogenperoxide in the presence of acetic acid. Pivaloyl chloride is acommercially available material; alternately it can be prepared byreacting the acid with excess thionyl. chloride according to the processdescribed by R. E. Kent and S. M. McElvain,

Org. Synth. Coll. Vol. 3, p. 490 (1955). Pivaloyl bromide can also besynthesized according to the same procedure using thionyl bromideinstead of thionyl chloride.

Preferably the preparation of the compound of this invention is carriedout using an excess of base as a solvent. By excess of base is meantmore than an equimolar amount of base. Optionally, an inert diluent canbe employed as a co-solvent together with at least an equimolar amountof base. Suitable inert diluents include dimethyl formamide, dimethylsulfoxide, dimethyl acetamide, hexamethylphosphoramide, etc;

Compound I is readily obtained in high yields and excellent purity, andis conveniently isolated from the reaction mixtures by techniques suchas distillation, crystallization, preparative column chromatography,etc.

For this application, the compound can be formulated for oral orparenteral administration according to conventional techniques.Effectiveness and toxicity of this compound is such that each dosageunit can contain from 5 to 500 mg. of active material. Compositions fororal administration can be solid or'liquid and can take the form ofsyrups, isotonic solutions, tablets, capsules etc. Suitable solidphysiologically acceptable carriers include lactose, magnesium stearate,sucrose, talc, stearic acid, gelatin, polyvinyl pyrrolidone etc.Exemplary liquid physiologically acceptable carriers are peanut oil,olive oil, sesame oil and water. Furthermore, the carrier may include atime delay material such as glyceryl monostearate or glyceryldistearate, alone or in combination with a wax.

Ifa solid carrier is used, the preparation can be tabletted, placed in ahard gelatin capsule or in the form of a troche or lozenge. The amountof solid carrier will vary widely but preferably will be from about 25mg. to about 1 gm. If a liquid carrier is used, the preparation may bein the form of a soft gelatin capsule, placed in an ampule or in aliquid suspension.

For parenteral administration, the carrier or excipient may be asterile, parenterally acceptable liquid, e.g. water or a parenterallyacceptable oil; e.g., arachis oil contained in ampules.

While any of the above compositions are efficacious, preferred aretablets for oral administration.

All tests were conducted on adult albino male mice (Charles Riverstrain); the dosage consisted of the active agent suspended in 10%aqueous acacia and was administered orally and/or subcutaneously asindicated.

Acute oral toxicity was determined in the conventional manner. Theresults were expressed as LD the dose required to produce death in 50%of the animals treated, determined graphically, with the limits shown inparentheses.

isf'maintairied 'a't' 54-55C. The reaction time of this noxious thermalstimulus is the time in seconds re- I barbituric acid, prepared'follorwing the procedure def scribed in Belgian Pat. No? 7 75,! 17, wasdissolved in a mixture of pivaloyl chloride ml.) and 60. ml. pyriine.The mixture was heated at 75C overnight, then cooled and poured into icecontaining 60 ml. of concentrated hydrochloric acid. The produce was ex,tracted four times with ethyl acetate, and the combined extracts washedwith saturated sodium chloride solu tion, sodium bicarbonate solution,dilute hydrochloric acid and sodium chloride solution. After drying overanhydrous sodium sulfate, solvent was removed by evaporation on a BuchiRotovapor apparatus. The resulting product was purified by columnchromatography (230 g. silica gel). Elution with 5% ethyl acetate inbenzene solution followed by recrystallization from benzene provided5-pivaloyloxy-5-( l-phenylethyl) barbituric acid, m.p. 205-207C..

Analysis. Calcd. for C C, O -,N c, 61.43; H, 6.07; N, 8.43; Found: C,61.83; H, 6.04; N, 8.39.

Pharmacological testing of this compound gave the following results: 25

Two established procedures were employed to determine analgeticactivity. The method, described by Eddy, N.B., and Leimbach, D., J.Pharmacol. Exptl ing modificatiplj sslin t tested;by placinface of .acgpperwatexibath, the temperature of which quired for either locking ofthe paws or jumping, such that all four paws leave the surface oftheplate. The drug is then administered orally or subcutaneously, generallyat five dosage levels, (10 mice perdosage level) and the reaction timesare redetermined at intervals of A hour, 1 hour, and 2 hours; the timeof peak activity is the time at which the greatest number of animals isprotected. From the pretreatment reaction times the mean and standarddeviations are computed. The cut-off time is taken to be the meanreaction time plus 2 standard deviation units. Reaction times equal toor exceeding this cut-off time are considered to represent analgeticresponses. The dosage required to produce an analgetic response in 50%of the animals (ED and 95% limits) is computed graphically.

In the second procedure, the method of Siegmund, E., et.al. reported inProc. Soc. Exptl. Biol. and Med.

95, 729, (1957) was generally followed. The method is D mg/kg based onthe antagonism by both non-narcotic and narcotic analgetics of asyndrome induced in mice follow- Acme TOXiCiIY ing intraperitonealinjection of phenyl-p-quinone. The t fiz' g xg 690660-840) syndrome ischaracterized by intermittent contractions ima ED (oral) 3.l

of the abdomen, twisting and turning of the trunk, and Hot-Plate ED.(not dose-related) extension of the hind legs, beginning 3 to 10 minutesf I t en urnone no ose-re 3 c after the in ection and persisting formore than one z' g' 26% active 3 0O Ins/kg hour. The test drug isadministered orally at four to five dosage levels. At the time of peakactivity, 0.25 ml. of a 0.02 per cent solution of phenyl-p-quinone in 5per cent (aqueous) ethyl alcohol is injected intraperitoneally.Inhibition of the syndrome is considered an 30% active at 200 ing/kg I10% active at 400 mg/kg Therapeutic Index LD /ED (oral) 230 Time 'ofPeak Activity V2 hour analgetic response.

The following example will serve to illustrate the practice of thisinvention.

EXAMPLE The amount of 5 g. of 5-hydroxy-5-( l-phenylethyl) Patent No.318941023 Dated ly 8, 1975 Invmnmr(s) Carlos M. Samour and Julius A.Vida It is certified that error appears in the above-identified patentand that said Letters Patent are hereby corrected as shown below:

Column 3, line 10, "locking" should be --licking;

Column 4, line 6, "produce" should be product-.

gigncd and Scaled this fourteenth Day Of October 1975 [SEAL] /4ttest:

RUTHC.MASON C.MARSHALLDANN Alresting Officer Commissioner ofPatenrs andTrademurkx

1. A COMPOUND HAVING THE NAME 5-PIVALOYLOXY-5-(1PHENYLETHYL) BARBITURICACID.